Airway cooling and rewarming. The second reaction sequence in exercise-induced asthma.

To determine if a relationship exists among the magnitude and rate of airway rewarming, and the severity of bronchial obstruction in thermally induced asthma, we had seven subjects perform three- to four-point stimulus response curves with isocapnic hyperventilation of frigid air with and without pretreatment with inhaled norepinephrine. The latter was employed to alter the heat supplied to the airway walls by producing vasoconstriction. 1-s forced expiratory volume (FEV1) was measured before and 5 min after the cessation of each bout of hyperpnea and before and after norepinephrine. On a separate day, the subjects repeated the above challenges while the temperatures of the airstream in the intrathoracic airways were measured. Prenorepinephrine, FEV1 progressively decreased in a stimulus response fashion as ventilation rose, while norepinephrine shifted this curve to the right. As the level of ventilation increased, the size of the temperature difference between the cooling of hyperpnea and the rewarming of recovery followed suit, and their magnitude was linearly related to the severity of bronchial narrowing. Reducing the mucosal blood supply of the airways with norepinephrine limited rewarming and attenuated the obstructive response. These data demonstrate that the airway narrowing that develops following hyperpnea and the magnitude of the thermal differences are related, and that alterations in blood supply directly affect bronchial heat flux and influence obstruction.

Heat and water flux in the intrathoracic airways and exercise-induced asthma.

To explore the relationship between the flux of heat and water within the respiratory tract during exercise and recovery to the development of exercise-induced asthma (EIA), we recorded airstream temperature at multiple points throughout the tracheobronchial tree in 10 normal and 10 asthmatic subjects before, during, and after cycle ergometry. In both groups, the intra-airway temperature fell progressively as ventilation increased, and there were no significant differences between the thermal profiles of the two populations at rest or during exercise. Calculation of water losses and the osmolality of the airway surface fluid failed to demonstrate significant airway drying in either group. With cessation of the work load, the airstream temperature increased abruptly, rising two times more rapidly in the asthmatics than the normals. Since the major source of heat in these experiments is the bronchial circulation, our findings suggest a reaction sequence consisting of vasoconstriction and airway cooling during exercise followed by a rapid resupply of heat when exercise ceases. The latter may cause the hyperplastic capillary bed in the airways of asthmatics to develop an exaggerated rebound hyperemia which may lead to airway edema and EIA.

Intra-airway thermodynamics during exercise and hyperventilation in asthmatics.

To determine whether exercise and hyperventilation produce the same intrathoracic thermal events in asthmatics, we used a thermal probe to record airstream temperatures during both stimuli at multiple points within the tracheobronchial tree. From these data, the global and regionally distributed exchanges of water and heat that occurred throughout the respiratory tract were calculated. During each provocation, intra-airway temperatures fell equivalently, thereby producing similar intrathoracic water fluxes and heat transfers. Neither stimulus was associated with airway drying, and both resulted in similar distributed losses of thermal energy from the tracheobronchial tree despite small regional heat and water exchanges. The degree of airway obstruction was identical after both challenges; however, the onset of airway narrowing was earlier with hyperventilation and developed in association with more rapid rewarming. These data demonstrate that the hyperpnea of exercise and hyperventilation produce identical thermal consequences within the respiratory tract of asthmatics.

Sympathoadrenal response to repetitive exercise in normal and asthmatic subjects.

To explore the role of catecholamine release in the pathogenesis of exercise-induced asthma, we had seven asthmatic and seven normal subjects undergo three hourly exercise challenges that were matched for inspired air temperature, minute ventilation, and relative work loads. Pulmonary mechanics and plasma epinephrine and norepinephrine were measured before, at end exercise, and serially after each challenge. There were no differences in the pattern of sympathoadrenal response of asthmatic and normal subjects, and both groups released sufficient quantities of epinephrine and norepinephrine into the peripheral circulation to allow these compounds to function as circulating hormones. As the catecholamines rose with repetitive exercise, progressive bronchodilation occurred in the asthmatics at the end of the work load, thus decreasing the apparent magnitude of the obstructive response. In addition to their effects on airway smooth muscle, the alpha-adrenergic actions of both catecholamines may have reduced airway wall hyperemia and edema. These data demonstrate that asthmatics do not have a defect in catecholamine release during exercise and that the physiological expression of exercise-induced asthma can be modulated by the sympathoadrenal epiphenomena that are associated with physical exertion.

Inhaled furosemide attenuates hyperpnea-induced obstruction and intra-airway thermal gradients.

Inhaled furosemide attenuates exercise- and isocapnic hyperventilation-induced asthma; however, the mechanism for this phenomenon is unknown. Because the magnitude of the intra-airway thermal gradient that develops between the cooling of hyperpnea and the rewarming that occurs once hyperventilation ceases is directly related to the severity of thermally induced obstruction in humans, we wondered if furosemide blunted these temperature changes. To explore this issue, eight asthmatic subjects had tracheobronchial airstream temperature measures as they performed isocapnic hyperventilation with frigid air alone (HV) or with pretreatment with inhaled saline (S + HV) or 45 +/- 3 (SE) mg of furosemide (F + HV). HV and S + HV resulted in similar degrees of obstruction, whereas the mechanical decrements after F + HV were significantly less. In concert with this protective effect, F + HV resulted in less airstream cooling during hyperventilation and slower rewarming in the recovery period. Because the major source of heat to the airways is provided by its microcirculation, inhaled furosemide may be acting as a topical vasodilator serving to enhance heat availability and thus reducing the effective thermal burden of hyperpnea.

Asthma.

There is an active inflammatory process in the airways of patients with asthma, even when the patients are asymptomatic. Some of the types of cells involved in this process possess the necessary biologic activities to produce many of the pathophysiologic features of asthma, but the underlying mechanisms have not yet been elucidated. Reducing the severity of the inflammatory process appears to be a reasonable goal of therapy, with potential long-range implications for the morbidity of asthma. Whether this theoretical benefit will be realized awaits further observation.

The effect of repetitive exercise on airway temperatures.

To determine if a relationship exists between intra-airway thermal events and the reduction in pulmonary mechanics that occur in asthmatics when they perform repetitive exercise, we recorded intrathoracic airstream temperatures in seven subjects during and after two identical bouts of cycle ergometry performed 30 min apart. From these data, global and regional thermal energy exchanges were calculated. Inspired air conditions, work loads, and minute ventilations were held constant for both trials. Pulmonary mechanics were measured prior to and serially after each challenge. As expected, the second provocation produced a smaller response than did the first. In association with these mechanical changes, the second challenge also produced less airway cooling and slower rewarming in the central airways. Hence, repetitive exercise trials performed over short intervals attenuate the essential thermal gradients necessary to produce obstruction. To the extent that these differences in intra-airway temperature reflect changes in perfusion, our data raise the possibility that the responsivity of the bronchial microcirculation of asthmatics may be altered by repetitive exercise.

Intrathoracic airstream temperatures during acute expansions of thoracic blood volume.

1. To determine the validity of employing intrathoracic heat flux as a reflection of changes in bronchial blood flow, we used a thermal probe to record airstream temperatures within the tracheobronchial tree in five normal and five asthmatic subjects during isocapnic hyperventilation challenges with and without inflation of the lower limb bladders of a pressure suit. 2. During hyperpnoea, airstream temperatures fell progressively in both subject groups. When blood volume was acutely shifted from the legs into the thorax via anti-shock trousers, airstream temperatures within the tracheobronchial tree rose and were significantly higher than the temperature recorded during hyperpnoea alone. In the normal subjects, once hyperpnoea ceased, the rate of airway re-warming was similar whether or not the anti-shock trousers were inflated. In the asthmatic subjects, however, shifting blood into the thorax attenuated the obstructive response to hyperpnoea and slowed the rate of re-warming. 3. These data demonstrate that changes in airway blood volume are reflected in fluctuations in intrathoracic heat exchange and that disruption of the end hyperpnoea thermal gradient attenuates the airway obstruction that follows hyperpnoea. Since the bronchial blood supply is the major source of heat to the airways, this circulation may play an important role in thermally induced asthma.

Vascular volume expansion and thermally induced asthma.

To determine whether a relationship exists between intravenous infusion of isotonic fluid and reactivity to hyperpnoea, eight normal and eight asthmatic subjects underwent rapid intravascular administration of approximately 2 l of warm normal saline, by itself and before and after hyperventilation of cold air. In the asthmatic subjects, saline infusion mirrored the obstruction seen with hyperventilation; whereas, in normal subjects saline produced more bronchial narrowing than hyperventilation. When the two stimuli were given together, the timing of the infusion altered the asthmatic subjects' responses. Giving fluid early in the hyperventilation challenge blunted obstruction, whereas giving it later amplified the airway narrowing. Similar findings, but on a smaller scale, occurred in normal subjects. These data demonstrate that sudden elevations in intrathoracic vascular volume with warm saline produce airway obstruction that is quantitatively similar to that seen with hyperventilation in asthmatic individuals. They also demonstrate that these two stimuli interact together in such a manner that a common mechanism may exist to account for the decrease in airflow.

Respiratory syncytial virus infection of human cord and adult blood monocytes and alveolar macrophages.

We studied the permissiveness of human leukocytes, blood monocytes, alveolar macrophages, and cord blood monocytes to infection with respiratory syncytial virus (RSV). Specific immunofluorescence was used to determine the percentage of infected leukocytes. The results indicated that monocytes were the most susceptible human leukocyte to in vitro infection with RSV. Polymorphonuclear leukocytes demonstrated no specific fluorescent staining after 24 h of exposure to RSV, whereas peripheral blood nonadherent mononuclear cells demonstrated a low percentage of positive cells, with a mean of 6 +/- 1% SE. In contrast, 37 +/- 5% of monocytes expressed RSV antigen after viral exposure. Exposure of monocytes to lipopolysaccharide (LPS) for 1 h prior to RSV increased the percentage of infected cells to 48 +/- 6% and stimulated their secretion of prostaglandin E2 (PGE2) and alpha tumor necrosis factor (TNF). Intrinsic mononuclear phagocytic factors influencing the permissiveness to RSV were studied by determining infection of adult and cord blood and alveolar mononuclear phagocytes (MP). Alveolar and blood MP simultaneously isolated from adult donors were similarly infected by RSV, which varied with the viral dose. Cord blood MP were more susceptible to RSV infection than were adult MP, 58 +/- 9% infected versus 37 +/- 5%, respectively (p less than 0.05). Treatment with LPS for 1 h prior to RSV exposure did not increase infection of cord blood MP as seen with adult blood MP. However, LPS can induce human monocytes to secrete cytokines with antiviral activity, and our results indicate that both gamma interferon and TNF, independently or in combination, prevented infection of monocytes in a dose-dependent manner.

Metabisulfite sensitivity and local dental anesthesia.

A case of sulfite sensitivity first manifesting as urticaria and acute airway obstruction following local anesthesia is described. A positive parenteral provocation test to metabisulfite was observed weeks after recovery of the patient from the clinical event.

Restricted replication of respiratory syncytial virus in human alveolar macrophages.

The cellular factors that regulate infection and replication of respiratory syncytial virus (RSV) in human alveolar macrophages were examined. RSV-exposed alveolar macrophages demonstrated a time-dependent expression of viral glycoproteins, maximal by 24 h post-infection resulting in infection of approx. 38% of the cells. Essentially all (33%) of these freshly isolated alveolar macrophages replicated RSV as shown by infectious centre assays. This RSV-permissive subpopulation of alveolar macrophages consisted primarily of major histocompatibility class II-expressing cells as determined by fluorescence-activated cell sorting. Re-infection of alveolar macrophages did not significantly alter the number of cells infected or capable of replicating RSV. However, in vitro differentiation of alveolar macrophages prior to infection resulted in a significant (P < 0.05), time-dependent decrease (approx. sevenfold) in the number of cells that replicated virus. The mechanism by which cellular differentiation restricted RSV replication is unknown. Production of defective interfering particles did not account for this decrease. Alveolar macrophages infected with RSV produce a variety of cytokines potentially contributing to this restricted viral replication. Pretreatment with several of these cytokines did not affect viral infection or replication. However, tumour necrosis factor (TNF alpha) significantly (P < 0.05) decreased viral replication but only by 30 to 60%. Thus RSV replication is reduced by in vitro differentiation of alveolar macrophages and, to a lesser degree, by pretreatment with TNF.

Virus-induced alterations in macrophage production of tumor necrosis factor and prostaglandin E2.

The cellular immune response to respiratory syncytial virus (RSV) is felt to contribute to viral clearance and/or the inflammation accompanying pulmonary infections with this virus. Both tumor necrosis factor (TNF) and prostaglandin E2 (PGE2) are important regulatory mediators of the cellular immune response. We examined the production of these mediators from purified human alveolar and blood mononuclear phagocytes (MP) after RSV infection in vitro and compared production induced by virus with that induced by lipopolysaccharide (LPS). RSV infection of alveolar MP did not alter PGE2 production but increased expression of TNF alpha mRNA paralleled by increased secretion of immunoreactive and biologically active TNF. TNF production by alveolar MP was dependent on the infectious dose of virus and occurred early in the viral replication cycle. In contrast, RSV had minimal effects on blood MP production of TNF and PGE2. However, blood MP (and not alveolar MP) infected with RSV and costimulated with LPS demonstrated a 1.7-fold increase in PGE2 levels compared with LPS alone (P less than 0.001). Therefore, RSV has differential effects on human alveolar and blood MP production of these immunoregulatory molecules.